Urgent Notification Intervention of Home Blood Pressure in Cohort Studies of the Tohoku Medical Megabank Project

Introduction: The Tohoku Medical Megabank (TMM) was established for creative reconstruction from the Great East Japan Earthquake and tsunami in 2011. Two prospective genome cohort studies in Miyagi prefecture have successfully recruited approximately 127,000 participants. The health status of these individuals was evaluated at the initial recruitment, and follow-up health checkups have been conducted every 5 years. During these health checkups, unexpected critical values were encountered, which prompted us to develop an urgent notification system. Methods: We analyzed the frequency of critical values observed in home blood pressure (HBP) test in an urgent notification office (UNO). We returned the critical values by urgent notification before the notifications of regular results. In addition, the impact of the TMM urgent notification on the participants was evaluated. Results: We issued urgent notifications of the critical values of extremely high HBP. Of the 21,061 participants who underwent HBP measurements, 256 (1.2%) met the criteria for urgent notification. It was found that abnormalities in blood sugar levels, renal function, and lipid values were frequently concurrent with the abnormal HBP readings. Annual questionnaires administered after the urgent notification, approximately 60% of those went to hospitals or clinics. Conclusions: The urgent notification system for hypertensive emergency with HBP in the TMM was well accepted by the participants and encouraged them to seek medical care. The system has been useful in addressing the prolonged healthcare problems and in promoting health care in large-scale disaster damaged areas.


Introduction
The Tohoku Medical Megabank (TMM) was established for reconstruction from the Great East Japan Earthquake (GEJE) and tsunami, which caused great damage to the northern pacific coast of Japan (1) .The TMM comprises two integral organizations at Tohoku University and Iwate Medical University, referred to as ToMMo (2), (3) and IMM (4) , respectively.ToM-Mo focuses on the survey of postdisaster health situations in Miyagi prefecture after the GEJE and contributes to future personalized healthcare and medicine by establishing prospective genome cohorts and a biobank (3), ( 5), ( 6), (7), (8), (9), (10), (11), (12) .Large-scale population cohort studies usually minimize interventions and excessive exposures to participants.Conversely, returning the health checkup results to participants is beneficial, making them knowledgeable of their health status and contributing to an overall improvement in their well-being.Therefore, considering the purpose of TMM that works on the survey of postdisaster health situations, the TMM made a conscious decision to return health checkup results to the par-ticipants (8) .For this purpose, ToMMo covering the participants in Miyagi prefecture has established a system returning health checkup results after the admission (6), (8) .
Our health checkup occasionally identifies participants with critically abnormal values or critical values.Therefore, in addition to the regular health check notification system, ToM-Mo developed an urgent notification system that informs participants about their abnormal results within 1 week after the identification of the critical values.We believe that this system will contribute to the maintenance of the participants' health.To the best of our knowledge, the urgent notification system is uncommon in prospective cohort studies.Therefore, the design and operation of the urgent notification system coupled with the return of ordinary results have been a fascinating challenge for ToMMo.
This study describes three critical features in the design and operation of the urgent notification system of ToMMo for hypertension.First, we selected critical values of home blood pressure (HBP) test among the various health checkups for the urgent notification, as it is medically important to notify participants when their high HBP is detected.Second, we rigorously established selection criteria for participants who should receive urgent notification.Lastly, we evaluated the impacts of urgent notification on the participants' behaviors.By elucidating these three aspects, we aimed to shed light on the significance of urgent notification for HBP.

Study design and population
Critical values for urgent notifications were screened while conducting health checkups of the TMM Community-Based Cohort Study (TMM CommCohort Study) (8) and Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study) (7), ( 13), (14) .Details of the health checkups were published elsewhere (6), (7) .This study included male and female patients aged at least 20 years who were living in Miyagi prefecture in Japan.The survey and recruitment were conducted between May 2013 and March 2016.Informed consent or ascent was obtained from the participants.This study was approved by the Institutional Review Board of the ToMMo (approval number: 2022-4-047; approval date: June 30, 2022).
We excluded the participants who withdrew consent by December 21, 2021 from total participants (n = 13,855) who underwent HBP measurements.Finally, 12,523 participants (3,728 men and 8,795 women) were analyzed.Those who withdrew consent by December 21, 2021, were excluded.Finally, 12,523 participants (3,728 men and 8,795 women) were analyzed.
Home blood pressure HBP was assessed using a cuff oscillometric device (HEM-7080IC; Omron Healthcare Co., Ltd.), which has been approved as a reliable equipment in Japan.The measure-ments were recorded for 14 days and subsequently analyzed.The hypertension criteria for conventional blood pressure of the 2009 Japanese Society of Hypertension (JSH2009) guidelines (15) were generally applied to our HBP survey.

Other measurements
Basic information including blood and urine laboratory test data was used as reference as previously described (3), ( 6), (7) .Nonfasting blood samples were obtained.The normal value ranges are listed in Table 1.The results of the health examination were regularly returned to the participants.A self-reported questionnaire was used to assess the patients' demographic characteristics, smoking and drinking status, educational level, physical activity, and history of respiratory disease (6) .Age was determined at the time of visit to the community support center.

Statistical analysis
To analyze the relation of two or more abnormal values, Pearson's chi-squared test or Fisher's exact test was conducted on the number of participants in 2 × 2 tables.The calculated Pvalues are also included in Table 2. Bonferroni-adjusted significance level (α) was set to 0.05/10 (0.005).P < 0.005 was considered to indicate statistical significance.Any changes resulting from urgent notification letters in receiving medical care for hypertension were analyzed using McNemar's chisquared test.All analyses were conducted using the R software version 4.3.2(R Core Team, Vienna, Austria).

Information management for TMM cohort studies
Participant recruitment was conducted from May 2013 to May 2017 in Miyagi prefecture (6), ( 7), (8) .Of the participants, approximately 127,000 (as of June 1, 2023) were recruited in Miyagi prefecture by ToMMo (Figure 1).These individuals were recruited either on the sites for specific health checkups for the annual community health examination conducted by the municipal organization or through direct visits for health examination to the community support centers located at seven sites in Miyagi prefecture (3) .Blood samples were obtained from 93,732 (as of June 1, 2023) individuals who participated in the TMM CommCohort Study and TMM BirThree Cohort Study.

HBP monitoring in TMM
In addition to conducting blood tests, we monitored the HBP of the participants aged >20 years who were undergoing health examination at our seven community support centers (Figure 2) (6) .Participants aged under 19 years were also included in the HBP monitoring, if they attended in the BirThree Cohort Study as parents.Eventually, 21,061 participants were subjected to HBP monitoring using automated sphyg- The number of participants is shown in the table.The symbols "+" and "−" in the column and raw labels indicate "presence" and "absence" of the abnormalities, respectively.Statistical analyses of participant count in 2 × 2 tables were conducted using 1 Pearson's chi-squared test or 2 Fisher's exact test, and the corresponding P-values were calculated.
momanometers supplied by ToMMo (Figure 1).The participants were instructed to measure their HBP every day, at least once in the morning and once in the evening for 14 days.Any additional measurements during midday/ afternoon were appreciated.The morning, midday/afternoon, and evening time periods were defined as 4:00 AM-11:00 AM, 11:00 AM-4:00 PM, and 4:00 PM-4:00 AM of the next day, respectively.The devices were returned to our community support centers after the monitoring (Figure 2).Subsequently, the measurements were extracted from the device and analyzed within 1-3 days after the return of the device.In the case where the participants measured their HBP two or more times within the same time period on the same day, the first measurement value was used.The average values of HBP in each time period were determined for 14 days.When the average HBP value in any time periods was greater than the urgent notification criterion, the information was immediately notified to the UNO.

Algorithm for urgent notification of blood pressure results
We designed a system in which we can return abnormal values in the blood test and HBP to the patients.In this system, if there are abnormal values in the blood test or HBP, a notification will be immediately sent to urgent notification office (UNO), which comprises several physicians and a specialist.The activities of the UNO are summarized in Figure 3.After receiving the data, more than two UNO members available at the time discuss the data and decide whether the data should be returned to the participants.If it is decided to return the data immediately, an urgent notification letter is prepared.Before being sent out, the letter is confirmed by multiple UNO members.
During the baseline health assessments from May 2013 to May 2017, 297 reports of suspicious cases of hypertensive emergency were reviewed.Upon making the decision in UNO (Figure 3), all available data in our baseline assessment were comprehensively considered, which included other inspection results, medical history, and medication records.We sent an urgent notification letter within 0-1 business day after the information was received by UNO (Figure 2).The participants were directly contacted to inquire about their medical conditions as needed.
In the urgent notification letter, suspected disease name(s) and brief interpretation regarding the abnormal data were described.Concurrently, recommendation as to which type of medical care would be adequate for the participant was given.Representative letters of urgent notification for HBP are shown in Figure 4.These letters were delivered through the Japanese postal service, which took 1 to 2 days to arrive.As shown in Figure 2, the participants may receive the urgent notification letters within 1 week after return of the sphygmomanometer device to the community support centers ( 16), ( 17), ( 18), (19) .

Urgent notification cases for HBP
We instructed the 21,061 participants (14,320 women and 6,741 men) to measure their HBP (Figure 1 and 5).Because of the design of our cohort study, the numbers of male and female participants exhibited two peaks, one in the 30s and the other in the 60s.Approximately 40% of the participants were aged >60 years; thus, it is likely that some of the participants had high blood pressure.The frequency of HBP recording varied among the participants; some measured it regularly throughout the day and weeks, whereas others performed the measurements less frequently.
The criteria for the decision to whether send the urgent notification letter or not were established.The urgent notification letters were sent to the participants who had average HBP values of at least three measurements that met the criteria for hypertension.If the average was based on two or fewer measurements, even if it met the criteria for hypertensive emergency, we did not send urgent notification letters.
As the participants took the HBP monitoring device home and measured their blood pressure for 14 days, the blood pressure measurements were analyzed almost 3 weeks after the blood test at the community support centers (Figure 2).The blood test reports were already completed and stored in the ToMMo database.Therefore, laboratory test data with abnormal but not urgent results were included in the urgent notification letters for high blood pressure as needed (Figure 4).

i) Urgent notification for hypertensive emergency
The HBP measurement was started at the community support centers in October 2013.At the beginning (from October 2013 to May 2014), we returned urgent notification letters when the mean HBP value were met the criteria of Grade II hypertension equivalent or higher (blood pressure ≥ 160/100 mmHg), based on the 2009 Japanese Society of Hypertension (JSH2009) Guidelines (15) .During this period, urgent notification letters were sent to 210 participants who had high blood pressure.Of these participants, 196 had Grade II hypertension (blood pressure >160/100 mmHg but <180/110 mmHg) and 14 had Grade III hypertension (blood pressure > 180/110 mmHg) according to the JSH2009 Guidelines.After our urgent notification operation for approximately 9 months, we realized that notification of the regular health assessment report within 3 months is sufficient for notifying the risk of hypertension of Grade II participants.Therefore, in July 2014, we revised our criteria for the urgent notification of HBP values and decided to send urgent notification letters only to participants with Grade III hypertension.Consequently, we sent urgent notification letters to 46 participants afterward.In the end, a total of 256 participants out of 299 received the urgent notification letters.

ii) Associating findings with hypertension
In this study, we sent urgent notification letters to 256 participants, of whom 60 and 196 had Grades III and II hypertension, respectively.However, two participants withdrew from the study, leaving us with 254 participants, of whom 198 (78%) had additional abnormal findings in their laboratory test data (Table 1 and 2).The most frequently observed abnormality was related to glucose metabolism (n = 118).Renal dysfunction (n = 101) and abnormal serum lipid levels (n = 90) were also found.Many participants had multiple types of abnormal findings.Notably, the chi-squared or Fisher's exact test for 2 × 2 contingency tables revealed a significant association between abnormal blood sugar level and abnormal lipid level (Table 2), which are suggestive of metabolic syndrome.As this is the first cross-sectional cohort survey we conducted, it is difficult to draw conclusions regarding the association be-tween elevated blood pressure levels and abnormal laboratory test data.

iii) Effect of urgent notification on the participants' behavior
As part of the ToMMo cohort program, we conducted annual questionnaire surveys on individuals who participated in the initial cross-sectional cohort survey (3), ( 6), (7), (8) .We could analyze annual questionnaires related to the status of hypertension treatment from the 254 participants who received urgent notification letters (Table 3).We compared the questionnaires at the pre-survey with those after the urgent notification.We obtained responses to the questionnaires from 228 and 163 participants before and after sending the urgent notification letters, respectively.The pre-survey questionnaires indicated that 95 participants were already "under regular treatment" in the medical clinic before receiving the urgent notification letters.Notably, this number increased to 116 out of the 163 participants who responded to the questionnaires after the urgent notification letters (Table 3).Contrarily, the number of participants who reported "discontinuation of follow-up," "doctor's follow-up without medication," or "never being pointed out" in response to inquiries about their hypertension status significantly decreased.Thus, our urgent notification letter appeared to have motivated the participants who were previously unconcerned about their blood pressure to seek medical attention.However, because of the inherent nature of the cohort studies, the number of participants who did not provide any response or feedback increased from 26 to 91.
Among the 254 participants who received urgent notifica- The decision on whether to send an urgent notification letter to a participant was made by the UNO, where several physicians and a specialist comprehensively discussed all the data available in our baseline assessment, including other inspection results, medical history, and medication records.If a decision was made to return the data, an urgent notification letter was prepared within 1 business day, and the letter was confirmed by multiple UNO members.tion letters, 151 were divided into subgroups, namely, those who responded to the pre-survey questionnaire, those who responded to the post-urgent notification questionnaire, and those who responded to both questionnaires, and their behaviors toward hypertension were examined (Table 3).The number of participants who were "under regular treatment" increased from 68 to 107, whereas that of participants who reported "never being pointed out" significantly decreased from 37 to 13.There is an increasing trend for the regular treatment after the notification.However, the increase in the number of participants who were "under regular treatment" after the ur-gent notification did not exhibit statistical significance compared with total of other four behaviors analyzed using McNemar's chi-squared test (P = 0.08).

Discussion
Elucidating how the GEJE has affected the residents' longterm health is a challenging issue, and it is particularly intriguing how the participants think about their health management after the earthquake.In the TMM project, we conducted health checkups at baseline and during the follow-up surveys As for the numbers of participants, two age peaks, 30's and 60's years old, were observed both in men and women.The numbers of the female participants were approximately twice more than that of the male participants.Approximately 40% of the participants were aged >60 years.Answer to questionnaires regarding the treatment statues of hypertension from participants (n = 254) who received urgent notification letters of high systolic and/or diastolic blood pressure, >180 (some were >160; see text) and/or >95, respectively.The 1 numbers of participants who responded to the 1 questionnaires of the pre-survey and of the post-emergent notification are shown in the top two rows.The percentages of participants who responded (n = 228 and n = 163 for pre-survey and post-urgent notification, respectively) are presented in the parentheses. 3Number of participants who responded to both the pre-survey and the post-urgent notification are subgrouped, and their answers in the pre-survey and post-urgent notification are shown in the bottom two rows.The 4 percentages of participants in the subgroup are presented in the parentheses. 5Not applicable.

Figure 1 .
Figure 1.Eligibility and enrollment of participants for home blood pressure.The percentage shown was calculated based on the number of participants for home blood pressure (HBP) measurement (n = 21,061) * and that of participants who received urgent notification letters (excluding 2 withdrawn participants, n = 254) † .

Figure 2 .
Figure 2. Diagram of operation time required in each step.Reports showing high values of blood test and home blood pressure (HBP) were transferred to the urgent notification office (UNO) from the ToMMo integrated database and community support centers, respectively.After assessments, an urgent notification letter was sent via mail to the participant, if necessary.The urgent notification letters arrived at the participants' address within1 week after return of the sphygmomanometer device to the community support centers.

Figure 3 .
Figure 3. Workflow of the urgent notification system.The decision on whether to send an urgent notification letter to a participant was made by the UNO, where several physicians and a specialist comprehensively discussed all the data available in our baseline assessment, including other inspection results, medical history, and medication records.If a decision was made to return the data, an urgent notification letter was prepared within 1 business day, and the letter was confirmed by multiple UNO members.

Figure 4 .
Figure 4. Example of the urgent notification letter sent to participants with abnormal home blood pressure value.In addition to the urgent HBP values, we stated the abnormal laboratory values in the letter, if present.

Figure 5 .
Figure 5. Numbers of participants and their gender distributions.As for the numbers of participants, two age peaks, 30's and 60's years old, were observed both in men and women.The numbers of the female participants were approximately twice more than that of the male participants.Approximately 40% of the participants were aged >60 years.

Table 1 .
Limits of Blood Test Values Used in ToMMo.
The recommended values for normal ranges from two clinical testing companies, Bio Medical Laboratories, Inc., Sendai, Japan, and LSI Medience, Sendai, Japan, were used as our reference ranges for normal values.

Table 2 .
Summary of Accompanying Abnormal Finding in Health Examination in Participants Receiving Home Blood Pressure Urgent Notification.

Table 3 .
Effect of Urgent Notification on the Participants' Behavior.